Cerebral microhemorrhages (CMB) detected using brain MRI are increasingly recognized as important markers of subclinical cerebrovascular disease. CMB are more frequent in advanced age, and are attributed to hypertensive vasculopathy or cerebral amyloid angiopathy. They have been related to an increased risk of stroke (especially brain hemorrhage) cognitive impairment and dementia. Their presence complicates prevention and treatment efforts for ischemic stroke and Alzheimer's disease. However the underlying pathophysiology, incidence and genetic determinants of CMB are not well understood. In the Framingham Heart Study, we have collected longitudinal data on cardiovascular risk factors, and also have genetic, biomarker and subclinical cardiovascular disease measures. Participants have had brain MRI, and simultaneous measures of cognitive performance. In the proposed grant we hypothesize that the prevalence and incidence of CMB increase with age, and relate to cardiovascular risk factors. We will investigate the relation of CMB to subclinical measures of atherosclerosis and hypertensive organ damage, and to novel circulating biomarkers of inflammation and vascular dysfunction. We will also relate CMB to other MRI measures of brain ischemic damage and aging, and cognitive performance. Finally we will study genetic determinants of CMB using already available genome-wide association data. The present project will be part of a career advancement program for Dr. Romero. He has training as a Vascular Neurologist and is an Assistant professor of Neurology at the Boston University Medical Campus. He has a long-standing interest in subclinical cerebrovascular disease, and in cerebrovascular disease prevention. Dr. Romero has already been actively involved in clinical research at the Framingham Heart Study and now proposes to obtain the training required to become an independent investigator in this team. He has short term plans to develop expertise in Neuroepidemiology through a structured program at the Boston University School of Public Health and is committed to a long term career as a clinical investigator in Vascular Neurology, studying CMB. The present project is to be conducted in the context of the Framingham Heart Study, using the resources of the study and involving the mentorship of a group of internationally recognized experts in Neuroepidemiology, Biostatistics, Neuroradiology, and Genetic Epidemiology. The proposed research project will not only advance our understanding of the pathophysiology of CMB, but also serve as the basis for further comprehensive studies of CMB as subclinical markers of cerebrovascular disease.